An ALPS-like patient without an identified mutation has been found to have a unique in vitro defect in T cell apoptosis associated with IL-2 withdrawal but normal T cell and B cell apoptosis in response to staurosporine, etoposide, cisplatin and radiation. This suggests the possibility of a distinct defect in the mitochondrial cell death pathway with a number of candidate proteins that could account for this in vitro defect. This lead to protein analysis by Western blot using B cell lines from the patient that revealed normal levels of Bim, Bad, phosphorylated-Bad, Bak, Bax and Bcl-2. In addition sequencing of genomic DNA revealed no evidence of a mutation in the gene encoding Bim and using cDNA, no evidence of a mutation in the gene encoding Bak. In light of the clearly demonstrated defect in apoptosis uniquely associated with cytokine withdrawal and the negative studies of candidate proteins, we have begun evaluation of this patients lymphocytes compared to normals using apoptosis-specific and whole human genome microarrays. At the same time we are further evaluating the nature of cytokine withdrawal induced cell death based on this patients since the in vitro functional findings suggest that this death pathway has distinct features that differ from other mitochondrial death pathways induced by drugs (etoposide, cisplatin) and irradiation.